Effects of COVID-19 on Parkinson’s disease clinical features: a

community-based case-control study

Roberto Cilia1, MD; Salvatore Bonvegna1,*, MD; Giulia Straccia1,2,*, MD; Golfrè Andreasi Nico1,*, MD;
Antonio E. Elia1, MD, PhD; Luigi M. Romito1, MD, PhD; Grazia Devigili1, MD, PhD; Emanuele
Accepted Article
Cereda3, MD, PhD; Roberto Eleopra, 1 MD.

1. Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Clinical Neurosciences,

Parkinson and Movement Disorders Unit, Milan, Italy;
2. Department of Medical Sciences and Advanced Surgery, University of Campania "Luigi Vanvitelli",
Napoli, Italy
3. Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;
* Equal contribution

Corresponding author:
Roberto Cilia, MD
Fondazione IRCCS Istituto Neurologico Carlo Besta, Parkinson and Movement Disorders Unit, via
Celoria 11, 20133, Milan, Italy; Tel. (+39) 23942368; Fax (+39) 23942539; Email:
roberto.cilia@istituto-besta.it

Title character count: 98; Abstract word count: 150; Manuscript word count: 1700;
References: 31; Number of Tables and Figures: Tables 2

Running title: COVID-19 effects on PD symptoms

Key words: COVID-19; Parkinson's disease, case-control study, motor symptoms, nonmotor symptoms

Financial disclosures/Conflict of interest RC has received fees for speaking at conferences from
Zambon, Bial, UCB, and Lusofarmaco; has received fees for consultancies from Roche, Z-Cube; has
received congress sponsorship from Zambon, and Boston Scientific. The other authors reported no
conflicts of interest.
Funding. This study was not funded.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article
as doi: 10.1002/mds.28170

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 Abstract
The impact of Coronavirus disease 2019 (COVID-19) on clinical features of Parkinson’s disease (PD)
has been poorly characterized so far. Out of 141 PD patients resident in Lombardy, we found twelve
COVID-19 cases (8.5%), whose mean age and disease duration (65.5 and 6.3 years, respectively) were
similar to controls. Changes in clinical features in the period January-April 2020 were compared with
those of 36 PD control subjects, matched for sex, age, and disease-duration, using the clinical
Accepted Article
impression of severity index for PD, the Movement Disorders Society Unified PD Rating Scale parts II
and IV, and the non-motor symptoms scale. Motor and nonmotor symptoms significantly worsened in
the COVID-19 group, requiring therapy adjustment in one-third of cases. Clinical deterioration was
explained by both infection-related mechanisms and impaired pharmacokinetics of dopaminergic
therapy. Urinary issues and fatigue were the most prominent nonmotor issues. Cognitive functions were
marginally involved, while none experienced autonomic failure.

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 Introduction
Since the first patient was diagnosed with COVID-19 in Lombardy, on February 20th 2020, Italy has
become the third most affected country (>215.000 cases) and 30.000 deaths in the world, as of May 8th,
2020.[1] COVID-19 neurotropic properties may underlie a worsening of chronic neurological diseases,
such as Parkinson’s disease (PD). COVID-19 may worsen PD by a number of mechanisms,[2-4]
including pharmacodynamics changes (e.g., reciprocal interactions between the dopaminergic and renin-
Accepted Article
angiotensin systems in the substantia nigra and striatum[5]) as well as systemic inflammatory
response.[6-9] Patients with PD are frailer than general population because of disease-related factors and
age-related co-morbidities.[2-4;10,11] A higher COVID-19 mortality rate has been described in
advanced PD patients in association to older age and longer disease duration.[12]
Our primary objective was to investigate the effects of COVID-19 on motor and nonmotor
symptoms in a community-based PD cohort. In addition, we explored whether older age and longer
disease duration represented risk factors for developing symptomatic COVID-19.

Materials and method

In the present observational, community-based, case-control study, we investigated demographic and
clinical features in a cohort of patients with idiopathic PD[13] and COVID-19 as compared to control
PD subjects between the pre-outbreak period in Italy (January 01st, 2020) and the end of lockdown
restrictions (May 4th, 2020). A 3-month period was chosen to minimize the effect of PD progression on
the change in clinical features and the recall bias. Diagnosis of COVID-19 was performed according to
clinical and laboratory criteria for probable and confirmed cases, released by the World Health
Organization criteria on March 20th, 2020.[14] In symptomatic cases fulfilling criteria for ‘probable
case’[14,15] we included only patients with close and protracted contacts (i.e., caregivers) with
laboratory-confirmed cases.
Out of the 1092 records obtained by searching the Besta Institute clinical software for patients
fulfilling the following criteria (i) International Classification of Diseases, Ninth-Revision, Clinical
Modification code for parkinsonism 332.0, (ii) resident in the Lombardy region, northern Italy (which is
by far the most affected area (>80.000 cases) with the highest case-fatality (>15.000 deaths) in Italy, as
of to May 11th, 2020),[16] (ii) visited at least once from January 01st, 2019 to December 31st, 2019, we
performed a random selection of 150 PD for subsequent remote interview by a neurologist experienced
in movement disorders (by video-consultation or telephone),[2,17,18] which was performed between
April 15th and May 4th, 2020. Signed informed consent was obtained prior to remote assessment and
collection of clinical data, as approved by the local Ethics Committee.
Out of a total of 141 subjects who accepted to be interviewed, twelve (8.5%) were affected by
COVID-19.[14] Compared to overall cohort of 129 PD control subjects (males 56.6%; age 69.1±10.1

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 years; PD duration 8.2±5.0 years; any comorbidity 62.8%), cases has similar sex distribution (P=0.37),
age (P=0.24), PD duration (P=0.20), and co-morbidities (P=0.54). Among those 129 screening negative
for COVID-19, a group of 36 PD controls matched for sex, age and disease duration (±1 year) was used
for subsequent statistical analysis. A 1:3 ratio was chosen to minimise the effects related to biological
variability and the potential presence of asymptomatic COVID-19 among controls.[19] Cases and
matched controls underwent in-depth assessment using the following internationally-validated scales.
Accepted Article
Motor aspects of experiences of daily living and the severity of treatment-related motor complications
were assessed using the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) parts II
and IV, respectively;[20] non-motor symptoms (NMS) were assessed using of the Italian version of the
NMS Scale (NMSS);[21] overall changes of motor and nonmotor features was additionally rated using
the Clinical Impression of Severity Index for Parkinson’s Disease (CISI-PD).[22]
Descriptive statistics were provided for continuous (mean and standard deviation) and
categorical (count and percentage) variables, which were compared between groups using the Student’s
t-test and the Fisher’s exact test. Then, between-visit changes in study parameters (January-to-April,
2020) were compared between COVID-19 cases and controls using repeated-measure linear regression
models. The role of potential confounders was addressed by MANOVA. All statistical analyses were
performed using STATA statistical software release 15.1 (Stata Corporation, College Station, TX)
setting the level of significance at a two-tailed P-value <0.05.

Results
Demographic and clinical features at baseline were similar between PD cases and matched control
subjects, except for the greater need to increase dopaminergic therapy dosing and higher rate of contacts
with confirmed COVID-19 among cases (Table 1). COVID-19 symptoms were mild, managed at home
without symptomatic therapy in 3 cases (25%); 8 cases (66.7%) had moderate illness, pharmacologically
managed at home by the general practitioner; only one patient was hospitalized (8.3%) due to
pneumonia. COVID symptoms remitted in ten out of 12 (83.3%) cases and were still ongoing in two
patients (16.7%; both remitted at subsequent follow-up on May 15th); nobody died.
At within-group comparison, cases evidenced a significant worsening of the CISI-PD total and
motor-signs scores, MDS-UPDRS part-II score, the NMSS total score and the urinary domain sub-score
(Table 2, footnote d). Between-group case-control analysis additionally revealed greater motor
disability (at CISI-PD), motor fluctuations (at MDS-UPDRS part-IV), and nonmotor complaints.
Involvement of cognitive functions was marginal (no change at CISI-PD), and autonomic cardiovascular
and sexual functions remained unaffected (Table 2).
Finally, considering the greater rate of diarrhoea among COVID-19 cases (Table 1) and its
detrimental effect on the pharmacokinetics of dopaminergic medications (particularly levodopa), we

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 adjusted a selected subset of models for this symptom and found that worsening of CISI-PD total and
motor signs scores was partially mediated by diarrhoea (p=0.002 for both) although COVID-19 status
was still a significant contributor (p=0.025 and 0.026, respectively). Worsening of MDS-UPDRS part II
and the part IV total score and the NMSS total score were explained by COVID-19 alone (p=0.008,
p=0.034, p=0.008, respectively); interestingly, increase in daily OFF-time was fully explained by
diarrhoea (p=0.019). We additionally explored whether urinary dysfunction and fatigue were due to
Accepted Article
COVID-19 or to diminished dopaminergic drive (Table 2) and found that urinary problems worsening
was due by both motor fluctuations (p<0.001) and COVID-19 (p=0.005), while fatigue was due to
COVID-19 alone (p<0.001).

Discussion
To our knowledge, this is the first community-based case-control study describing the effects of
symptomatic COVID-19 on PD motor and nonmotor symptoms. First, PD patients who develop
symptomatic COVID-19 were neither older age nor with longer disease duration than those screening
negative, but rather had nonsignificant 3.5-year younger age and 2.0-year shorter disease duration. The
lack of case fatalities is consistent with the Italian case-fatality rate of 3.5% at 60-69 years of age.[15]
Similarly, only one patient (8.3%) needed to be admitted to hospital for severe COVID-19 illness, which
is in line with the frequency of hospitalization previously reported in general population of the
Lombardy region.[23] We expand previous report in advanced PD[12] and show that mild-to-moderate
COVID-19 may be contracted independently of age and PD duration and that PD patients with mid-
stage PD do not seem to have an overall worse outcome than non-PD population.[15] Concerning the
primary objective of the study, we found a worsening of motor and nonmotor symptoms of PD in the
COVID-19 group compared to matched control subjects over the study period.
Motor symptoms. COVID-19 induced a significant worsening of motor performance, motor-
related disability and experiences of daily living. Worsening of levodopa-responsive motor symptoms
and increased daily OFF-time, caused either by the effects of acute systemic inflammatory response[6-
9] or by changes in pharmacokinetics, was so pronounced in one-third of cases to prompt neurologists to
increase dopaminergic therapy. We explored the relative contribution of suboptimal absorption of oral
therapy by adjusting motor endpoints for diarrhoea, which was present in 50% of cases. According to
multivariate analysis, concomitant diarrhoea explained the increase in motor fluctuations, but could not
entirely explain the worsening of motor disability and motor aspects of experiences of daily living.
Nonmotor symptoms. COVID-19 significant aggravated a number of nonmotor symptoms. Increased
fatigue in our cohort was fully explained by COVID-19, confirming that it a common COVID-19
symptom[24], as described in PD following systemic inflammation.[25] Urinary urge/incontinence and
nicturia were explained by the infection as well as increased motor fluctuations, which were partly due

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 to pharmacokinetic issues. COVID-19 was neither a major cause of cognitive dysfunction nor
autonomic failure in our cohort of mid-stage PD. Although there was an effect of COVID-19 on
attention, it was not severe enough to be detected by CISI-PD. We neither found changes in
cardiovascular, gastrointestinal and sexual function domains at the NMSS nor differences in
hypotension between the groups.
Strengths and Limitations. The main limitation of this study is the small cohort of COVID-19
Accepted Article
patients, albeit statistical analysis could detect several significant changes. There are a number of
strengths worth mentioning. First, our case-control study protocol excluded the detrimental effects that
quarantine and lockdown restrictions might have played on a number of confounders that influence PD
motor and nonmotor symptoms, such as reduced physical activity, enhanced stress, confusion, anxiety,
and sleep disturbances.[26] Second, a community-based survey minimised selection bias related to the
inclusion of hospitalized patients with severe illness or institutionalised ones with advanced PD and
comorbidities, who are more susceptible to neurological manifestations worse outcome.[27,28] Our
cohort with mild-to-moderate illness is likely representative of the majority of PD affected by COVID-
19, considering that only a minority of cases require hospitalization [29-31]. Third, we excluded
secondary and atypical parkinsonisms (including dementia with Lewy bodies), minimising the risk of
overestimating either fluctuating or drug-induced worsening of cognitive dysfunction, visual
hallucinations, and autonomic failure. Finally, our comprehensive assessment performed by experienced
neurologists in a single tertiary referral clinic ensured a homogeneous and standardized approach.
Larger multicentre studies would have requested longer time for data collection, increasing
patients/caregivers recall bias.

Conclusions
PD patients may experience substantial worsening of motor and nonmotor symptoms during mild-to-
moderate COVID-19 illness, independently of age and disease duration. Clinicians should take
pharmacokinetic changes into consideration before adjusting therapy regimen (e.g., management of
dehydration secondary to fever, diarrhoea, anorexia with reduced water intake). Although we speculate
that subacute clinical changes in PD associated to nonsevere COVID-19 illness are likely caused by
systemic inflammatory response[8-9] rather than a direct invasion of the central nervous system,[27,28]
further studies in larger PD populations are warranted to clarify the cause-effect relationship among
clinical changes and the severity of COVID-19 illness, cytokine levels and virus detection in the
cerebrospinal fluid.

Acknowledgments. We are thankful to Francesca De Giorgi for providing the dataset of patients with
parkinsonism resident visited at the Besta Institute.

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 Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design,
B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and
Critique.
RC: 1A, 1B, 1C, 2A, 2B, 3A, 3B; SB: 1B, 1C, 3B; GS: 1C, 3B; NGA: 1C, 3B; AEE: 1C, 3B; LR: 1C,
3B; GD: 1C, 3B; EC: 2A, 2B, 3B; RE: 1A, 1B, 3B
Accepted Article

References
[1] Coronavirus COVID-19 global cases by the Center for Systems Science and Engineering (CSSE) at Johns
Hopkins. Updated May 7, 2020. Accessed May 7, 2020.
https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6
[2] Stoessl AJ, Bhatia KP, Merello M. Editorial: movement disorders in the world of COVID-19. Mov Disord
2020 Apr 6. [Epub ahead of print].
[3] Papa SM, Brundin P, Fung VSC, et al; and the MDS-Scientific Issues Committee. Impact of the COVID-19
Pandemic on Parkinson's Disease and Movement Disorders. Mov Disord. 2020 Apr 6. [Epub ahead of print]
[4] Helmich RC, Bloem BR. The impact of the COVID-19 pandemic on Parkinson’s disease: hidden sorrows and
emerging opportunities. J Parkinsons Dis 2020; 10(2):351–354.
[5] Labandeira-Garcia JL, Rodriguez-Pallares J, Dominguez-Meijide A, Valenzuela R, Villar-Cheda B,
Rodríguez-Perez AI. Dopamine-angiotensin interactions in the basal ganglia and their relevance for
Parkinson's disease. Mov Disord 2013; 28(10):1337-42.
[6] Lindqvist D, Kaufman E, Brundin L, Hall S, Surova Y, Hansson O. Non-motor symptoms in patients with
Parkinson's disease - correlations with inflammatory cytokines in serum. PLoS One 2012; 7(10):e47387.
[7] Green HF, Khosousi S, Svenningsson P. Plasma IL-6 and IL-17A Correlate with Severity of Motor and Non-
Motor Symptoms in Parkinson's Disease. J Parkinsons Dis 2019; 9(4):705-709.
[8] Brugger F, Erro R, Balint B, Kägi G, Barone P, Bhatia KP. Why is there motor deterioration in Parkinson's
disease during systemic infections-a hypothetical view. NPJ Parkinsons Dis 2015; 1:15014.
[9] Umemura A, Oeda T, Tomita S, Hayashi R, Kohsaka M, Park K, Sugiyama H, Sawada H. Delirium and high
fever are associated with subacute motor deterioration in Parkinson disease: a nested case-control study.
PLoS One. 2014; 9(6):e94944.
[10] Vijayan S, Singh B, Ghosh S, Stell R, Mastaglia FL. Brainstem ventilator dysfunction: A plausible
mechanism for dyspnea in Parkinson's Disease? Mov Disord. 2020; 35(3):379-388.
[11] Titova N, Qamar MA, Chaudhuri KR. The Nonmotor Features of Parkinson's Disease. Int Rev Neurobiol
2017; 132:33-54.
[12] Antonini A, Leta V, Teo J, Chaudhuri KR. Outcome of Parkinson's Disease patients affected by COVID-19.
Mov Disord 2020 Apr 29. [Epub ahead of print]
[13] Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS Clinical Diagnostic Criteria
for Parkinson’s Disease. Mov Disord 2015; 30: 1591-1600.

This article is protected by copyright. All rights reserved.

 [14] World ealth rganization. ( ). Global surveillance for COVID-19 caused by human infection with
COVID-19 virus: interim guidance, 20 March 2020. Accessed May 8, 2020. World Health Organization.
https://apps.who.int/iris/handle/10665/331506.
[15] Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to
COVID-19 in Italy. JAMA Neurology 2020; 323(18):1775-1776.
[16] Civile DdP. COVID-19 Italia - Monitoraggio della situazione [online]. Available at:
http://opendatadpc.maps.arcgis.com/apps/opsdashboard/index.html#/b0c68bce2cce478eaac82fe38d4138b1.
Accepted Article
Accessed May 12, 2020.
[17] Gabbrielli F, Bertinato L, De Filippis G, Bonomini M, Cipolla M. Istituto Superiore di Sanità. Interim
provisions on telemedicine healthcare services during COVID-19 health emergency. Version of April 13,
2020. 2020, ii, 29 p. Rapporti ISS COVID-19 n. 12/2020
[18] Bloem BR, Dorsey ER, Okun MS. The Coronavirus Disease 2019 Crisis as Catalyst for Telemedicine for
Chronic Neurological Disorders. JAMA Neurol. 2020 Apr 24. [Epub ahead of print]
[19] Nishiura H, Kobayashi T, Miyama T, Suzuki A, Jung SM, Hayashi K, Kinoshita R, Yang Y, Yuan B,
Akhmetzhanov AR, Linton NM. Estimation of the asymptomatic ratio of novel coronavirus infections
(COVID-19). Int J Infect Dis. 2020; 94:154-155.
[20] Goetz CG, Tilley BC, Shaftman S, et al. Movement Disorder Society UPDRS Revision Task Force.
Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008; 23:2129–2170.
[21] Cova I, Di Battista ME, Vanacore N, et al. Validation of the Italian version of the Non Motor Symptoms
Scale for Parkinson's disease. Parkinsonism Relat Disord 2017; 34:38-42.
[22] Martínez-Martín P, Forjaz MJ, Cubo E, Frades B, de Pedro Cuesta J; ELEP Project Members. Global versus
factor-related impression of severity in Parkinson's disease: a new clinimetric index (CISI-PD). Mov Disord
2006; 21(2):208-14.
[23] Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected
With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020 Apr 6. [Epub ahead of
print]
[24] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel
coronavirus in Wuhan, China. Lancet 2020; 395(10223):497-506.
[25] Felger JC, Miller AH. Cytokine effects on the basal ganglia and dopamine function: the subcortical source of
inflammatory malaise. Front Neuroendocrinol 2012; 33(3):315-27.
[26] Brooks SK, Webster RK, Smith LE, et al. The psychological impact of quarantine and how to reduce it: rapid
review of the evidence. Lancet 2020; 395(10227):912-920.
[27] Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B.
Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China.
JAMA Neurol. 2020 Apr 10. [Epub ahead of print]
[28] Asadi-Pooya AA, Simani L. Central nervous system manifestations of COVID-19: A systematic review. J
Neurol Sci 2020 Apr 11; 413:116832.

This article is protected by copyright. All rights reserved.

 [29] Bi Q, Wu Y, Mei S, et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close
contacts in Shenzhen, China: a retrospective cohort study [published online ahead of print, 2020 Apr 27].
Lancet Infect Dis 2020; S1473-3099(20)30287-5.
[30] Lechien JR, Chiesa-Estomba CM, Place S, et al. Clinical and Epidemiological Characteristics of 1,420
European Patients with mild-to-moderate Coronavirus Disease 2019. J Intern Med.
2020;10.1111/joim.13089 Apr 30 [Epub ahead of print].
[31] Kim GU, Kim MJ, Ra SH, et al. Clinical characteristics of asymptomatic and symptomatic patients with mild
Accepted Article
COVID-19. Clin Microbiol Infect. 2020; S1198-743X(20)30268-8. Apr 30 [Epub ahead of print]
Table 1. Characteristics of the study population.
Controls ( N = P-
Variable Cases ( N = 12 )
36 ) valuef
General features
Male gender, N (%) 5 (41.7) 15 (41.7) 1.00
Age, years [Mean (SD)] 65.5 (8.9) 66.3 (8.1) 0.78
Current Smoking, N (%) 0 (0.0) 3 (8.3) 0.56
Past Smoking, N (%) 5 (41.7) 10 (27.8) 0.48
Frequency of smoking, N cigarettes/day (%) 10.0 (8.7) 9.1 (7.3) 0.82
2
Body mass index, kg/m [Mean (SD)] 25.1 (3.8) 25.5 (3.8) 0.77
Body weight, kg [Mean (SD)] 67.0 (11.5) 71.3 (14.5) 0.36
Seasonal vaccinations in 2019, total N (%) 3 (25.0) 9 (25.0) 1.00
of whom, Anti-H1N1, N (%) 3 (25.0) 9 (25.0) 1.00
Anti-Pneumococcus, N (%) 1 (8.3) 2 (5.5) 1.00
a
PD-related features
Age at PD onset, years [Mean (SD)] 59.0 (8.1) 60.4 (7.8) 0.58
Tremor-dominant phenotype, N (%) 6 (50) 18 (50) 1.00
Disease duration, years [Mean (SD)] 6.3 (3.6) 6.1 (2.9) 0.79
Hoehn-Yahr stage, Mean (SD) 1.8 (0.7) 1.8 (0.6) 0.95
Dementia, N (%) 0 (0.0) 3 (8.3) 0.56
Therapy
Levodopa, N (%) 10 (83.3) 28 (77.8) 1.00
Levodopa dose, mg/day [Mean (SD)] 400.0 (119.3) 433.6 (227.1) 0.09
DA, N (%) 9 (75.0) 23 (63.9) 0.73
iMAO-B, N (%) 6 (50.0) 16 (44.4) 0.75
iCOMT, N (%) 0 (0.0) 4 (11.1) 0.56
Amantadine, N (%) 0 (0.0) 0 (0.0) 1.00
b
Advanced-stage Invasive Therapies, N (%) 1 (8.3) 1 (2.8) 0.44
Total LEDD, mg/day [Mean (SD)] 571 (517) 487 (327) 0.52
Therapy adjustment during the study period, N (%) 4 (33.3) 2 (5.5) 0.028
Risk factors for COVID-19
Contact with confirmed or suspect COVID-19, total N
8 (66.7) 4 (11.1) <0.001
(%) c
of whom, Confirmed COVID-19, N (%) 6 (50.0) 0 (0.0) <0.001

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 Suspect COVID-19, N (%) 2 (16.7) 4 (11.1) 0.63
Comorbidities
Any 9 (75) 24 (66.7) 0.73
COPD 1 (8.3) 4 (11.1) 1.00
Hypertension, N (%) 4 (33.3) 16 (44.4) 0.74
Obesity, N (%) 1 (8.3) 2 (5.5) 1.00
Diabetes mellitus, N (%) 0 (0.0) 2 (5.5) 1.00
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Cardiopathy, N (%) 1 (8.3) 5 (13.9) 1.00
Malignancies, N (%) 2 (16.7) 3 (8.3) 0.59
Immune system diseases, N (%) 1 (8.3) 1 (2.8) 1.00
d
Immune-modulating therapies, N (%) 2 (16.7) 2 (5.5) 0.26
Renal or Hepatic dysfunction, N (%) 1 (8.3) 5 (13.9) 1.00
e
Other neurological diseases, N (%) 1 (8.3) 4 (11.1) 1.00
COVID-19 symptoms
Fever, N (%) 10 (83.3) 2 (5.5) <0.001
Cough, N (%) 9 (75%) 3 (8.3) <0.001
Dyspnea, N (%) 4 (33.3) 0 (0.0) 0.003
Dizziness, N (%) 2 (16.6) 1 (2.8) 0.15
Headache, N (%) 4 (33.3) 3 (8.3) 0.055
Anorexia, N (%) 5 (41.6) 1 (2.8) 0.002
Diarrhoea, N (%) 6 (50) 2 (5.5) 0.002
Fatigue, N (%) 7 (58.4) 3 (8.3) <0.001
Skeletal muscle pain, N (%) 7 (58.4) 2 (5.5) <0.001
Nausea/Vomiting, N (%) 2 (16.6) 1 (2.8) 0.15
Smell loss, N (%) 4 (33.3) 1 (2.8) 0.011
Taste loss, N (%) 2 (16.6) 1 (2.8) 0.15
Hypotension, N (%) 2 (16.6) 1 (2.8) 0.15

Abbreviations: COPD, Chronic obstructive pulmonary disease, including asthma; DA, dopamine agonists; iCOMT,
catechol-O-methyltransferase inhibitors; ICU, intensive care unit; iMAO-B, Monoamine Oxidase type B
Inhibitors; LEDD, levodopa equivalent daily dose; PD, Parkinson’s disease; Pts, patients.
Data are shown as number of patients (N) and frequency (%) or as mean (standard deviation).
a
These data refer to the baseline state (January 2020) before the COVID outbreak in Italy
b
One case was on Levodopa/Carbidopa gel infusion; one control was on subthalamic nucleus stimulation.
c
Defined according to the WHO criteria.[14]
d
Including daily intake of drugs targeting rheumatic diseases or malignancies (e.g., steroids,
hydroxychloroquine, methotrexate, azathioprine, etc.) prior to the baseline assessment.
e
One patient with meningioma among cases, 4 patients with chronic cerebrovascular disease among controls.
f
Between-group comparisons of continuous variables were performed using the unpaired Student’s t-test, while
categorical variables were analyzed by the Fisher’s exact test.

Table 2. Analysis of study endpoints (CISI-PD, MDS-UPDRS, NMSS).

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 Cases ( N = 12 ) Controls ( N = 36 ) Statistics

Between-
Baseline End of Baseline End of group P-
Variable a Change b Change b
study a a
study a difference in value c
change b,c
a) CISI-PD
7.4 1.3 (0.3, 7.6 0.1 (0.0, <0.001
Total score 6.2 (4.1) 7.5 (4.7) 1.2 (0.6, 1.7)
2.2) d
Accepted Article
(4.1) (4.8) 0.2)
3.0 0.7 (0.2, 2.7 0.0 (- <0.001
Motor signs 2.3 (1.4) 2.7 (1.4) 0.6 (0.3, 0.9)
(1.3) 1.2) d (1.4) 0.0, 0.1)
2.4 0.3 (-0.1, 2.4 0.0 (0.0, 0.003
Disability 2.1 (1.1) 2.4 (1.4) 0.3 (0.1, 0.5)
(1.4) 0.7) (1.4) 0.0)
Motor 0.7 0.1 (-0.1, 1.0 0.0 (- 0.42
0.6 (1.2) 1.0 (1.4) 0.1 (-0.1, 0.2)
complications (1.4) 0.3) (1.4) 0.1, 0.1)
1.3 0.1 (-0.1, 1.5 0.0 (- 0.089
Cognitive status 1.2 (1.2) 1.5 (1.5) 0.1 (-0.0, 0.3)
(1.2) 0.4) (1.5) 0.1, 0.1)
b) MDS-UPDRS
11.9 13.7 1.8 (0.4, 12.0 12.2 0.2 (0.0, <0.001
UPDRS part II 1.6 (0.8, 2.3)
(7.6) (9.4) 3.1) d (8.3) (8.3) 0.4) d
4.2 1.2 (-0.2, 4.8 0.0 (0.0, 0.002
UPDRS part IV 3.0 (6.2) 4.8 (6.6) 1.2 (0.5, 2.9)
(8.1) 2.5) (6.6) 0.0)
UPDRS part IV - 1.5 0.4 (-0.2, 1.7 0.0 (0.0, 0.014
1.1 (2.0) 1.7 (2.5) 0.4 (0.1, 0.7)
OFF e (2.8) 1.0) (2.5) 0.0)
UPDRS part IV – 0.5 0.2 (-0.2, 0.6 0.0 (0.0, 0.083
0.3 (1.2) 0.6 (1.2) 0.2 (-0.0, 0.4)
DYSK e (1.7) 0.5) (1.2) 0.0)
c) NMSS
10.4 41.9 41.8 <0.001
39.3 49.7 -0.1 (- 10.5 (5.2,
Total score (0.2, (40.8) (41.1)
(28.1) (43.1) 0.7, 0.5) 15.9)
20.6) d
-0.4 (- 0.13
1.8 0.3 (-1.1, 0.9
Cardiovascular 1.5 (1.3) 1.3 (2.3) 0.6, - 0.6 (-0.2, 1.4)
(3.3) 1.6) (1.9)
0.2) d
10.5 2.2 (-0.2, 10.0 9.8 -0.1 (- 0.001
Sleep/Fatigue 8.3 (6.4) 2.3 (1.0, 3.6)
(7.1) 4.6) (9.7) (9.7) 0.4, 0.1)
8.6 11.8 3.2 (-1.2, 7.6 7.6 0.0 (- 0.010
Mood/Apathy 3.1 (0.8, 5.5)
(14.3) (17.9) 7.5) (11.0) (11.3) 0.4, 0.4)
Perceptual 0.9 0.0 (0.0, 0.7 0.0 (0.0, 1.00
0.9 (1.6) 0.7 (1.6) 0.0 (0.0, 0.0)
problems (1.6) 0.0) (1.6) 0.0)
4.7 1.5 (-1.1, 4.9 0.0 (- 0.038
3.2 (4.1) 4.9 (7.1) 1.4 (0.1, 2.8)
Attention/memory (7.8) 4.1) (7.1) 0.1, 0.2)
3.2 -0.1 (- 3.2 0.2 (- 0.17
Gastrointestinal f 3.3 (5.1) 3.0 (3.8) -0.4 (-0.9, 0.2)
(5.2) 0.8, 0.5) (3.9) 0.0, 0.4)
10.8 2.2 (0.1, 8.3 0.0 (0.0, <0.001
Urinary 8.6 (7.5) 8.3 (9.0) 2.3 (1.1, 3.4)
(9.3) 4.4) d (9.0) 0.0)
1.3 0.0 (0.0, 2.1 0.0 (0.0, 1.00
Sexual function 1.3 (2.0) 2.1 (4.5) 0.0 (0.0, 0.0)
(2.0) 0.0) (4.5) 0.0)
4.8 1.3 (-0.5, 4.3 0.1 (- 0.014
Miscellaneous 3.5 (3.3) 4.2 (5.9) 1.2 (0.2, 2.1)
(3.7) 3.0) (5.9) 0.0, 0.2)
Abbreviations: CISI-PD, Clinical Impression of Severity Index for Parkinson’s Disease. MDS-UPDRS, Movement Disorders
Society Unified PD Rating Scale; NMSS, non-motor symptoms scale.
a
Data are provided as mean (standard deviation)

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 b
Data are provided as mean (95% confidence interval)
c
According to repeated-measures linear regression model
d
Significantly different compared to baseline (test for within-group comparison)
e
OFF-related subscore was calculated as the sum of items 4.3, 4.4, 4.5. Dyskinesias subscore was calculated as the sum of
items 4.1, 4.2
f
Note that the gastrointestinal domain of the NMSS does not include assessment of diarrhoea.
Accepted Article

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